1. Field of Invention
This invention relates to penicillin-type compounds having lactic acidosis-inhibitory effects in ruminants and to intermediates and processes for preparing such compounds. In particular, this invention relates to 6-(N'-vinylureido)penicillanic acids and salts thereof; to derivatives and salts thereof; to intermediates for and methods of preparing such compounds. The invention also relates to pharmaceutical compositions containing such compounds and methods for inhibiting lactic acidosis in ruminants.
2. Prior Art
It is common practice in preparing range-fed cattle and other ruminants for market to hold them in "feed-lots" for certain periods of time where feed is restricted to "high energy" (carbohydrate) foods that promote rapid weight gain and develop other desirable characteristics in such animals. Consumption of large amounts of high energy feed stuffs required to promote these effects often results in acute indigestion in the ruminants. This disorder is attributable to a series of biochemical and microbiological events that are triggered by an initial rapid accumulation of lactic acid in the rumen. Symptoms of such lactic acidosis initially appear as decreased feed consumption and rate of weight gain (the "off-feed" syndrome) and may ultimately result in death. A considerable volume of information is available concerning the microbiological processes in the rumen that are associated with high energy, feed-caused acute indigestion. Ruminants not accustomed to these high energy diets have fewer numbers of amylolytic, volatile fatty acid (VFA)-producing rumen bacteria than animals that have already adapted to such diet. However, one saccharolytic, amylolytic, lactate-producing rumen organism, Streptococcus bovus, is present in approximately equal numbers in both high energy-fed and the range-fed animals. Since the total bacterial numbers are lower in range-fed animals, S. bovus is one of the predominant species under this latter feeding regimen. It is recognized that the potential growth rate of S. bovus is much more rapid than other rumen bacteria. An abundance of carbohydrate in the rumen of unadapted animals can therefore lead to an almost explosive growth of S. bovus with an accompanying increase in lactic acid production and consequent precipitous drop in pH within the rumen. The normal, major species of rumen microorganisms survive poorly, if at all, at this lowered pH. VFA production is therefore inhibited. Further, S. bovus fails to grow at the acidity that it ultimately produces. Consequently, lacto bacilli predominate and, if sufficient carbohydrate is available, lactic acid production continues with visible symptoms of lactic acidosis becoming extant. As an attempt to diminish the occurance of lactic acidosis, it has been the practice to increase the energy (carbohydrate) intake of feed-lot cattle gradually in order for the rumen microbial population to become adapted to the change in diet. This adaptation typically is ten days or longer in duration. Consequently, rapid initial weight gains for these ruminants are intentionally sacrificed so as to avoid occurrences of lactic acidosis. In addition, since animals are fed in large groups, sub-clinical occurrences of lactic acidosis still occur throughout the feeding period. It is therefore desirable to permit an alternative, less time-consuming method than the typical adaptation period for preventing accumulation of lactic acid in the rumen following engorgement of high-energy feed stuffs.